Phthalazine derivatives as phosphodiesterase 4 inhibitors

ABSTRACT

Compounds of formula (I) wherein B is alkylene, amino, CONH or a bond; Cy is optionally substituted phenyl or heteroaryl; R is H, phenyl or (C 1-4 )alkyl optionally substituted; R 1  is (C 1-6 )alkyl or polyfluoro(C 1-6 )-alkyl; R 2  is (C 4-7 )cycloalkyl optionally containing an oxygen atom and optionally substituted; and the N→O derivatives and pharmaceutically acceptable salt thereof are PDE 4 and TNFα inhibitors.

This is a 371 of International Application Serial No. PCT/EP98/08291,filed Dec. 17, 1998.

The present invention relates to phthalazine derivatives, topharmaceutical compositions comprising them and to their use asphosphodiesterase 4 inhibitors.

Phosphodiesterases are a family of isoenzymes which constitutes thebasis of the main mechanism of cAMP (cyclicadenosine-3′,5′-monophosphate) hydrolytic inactivation. cAMP has beenshown to be the second messenger mediating the biologic response to manyhormones, neurotransmitters and drugs [Krebs Endocrinology Proceedingsof the 4th International Congress Excerpta Medica, 17-29, 1973]. Whenthe suitable agonist binds the cell surface, the adenylated cyclaseactivates and turns Mg²⁺-ATP into cAMP. cAMP modulates the activity ofthe majority, if not of all, of the cells contributing to thepathophysiology of various respiratory diseases both of allergic originand not. It follows that an increase of CAMP concentration yieldsbeneficial effects such as airway smooth muscle relaxation, inhibitionof the mast cell mediator release (basophil granulose cells),suppression of the neutrophil and basophil degranulation, inhibition ofthe monocyte and macrophage activation. Thus, compounds capable ofactivating adenylate cyclase or of inhibiting phosphodiesterases couldsuppress the undesired activation of the airway smooth muscle and of agreat number of inflammatory cells.

In the phosphodiesterase family there is a distinct group of isoenzymes,phosphodiesterases 4 (hereinafter PDE 4), specific for the hydrolysis ofthe airway smooth muscle and inflammatory cells cAMP (Torphy,“Phosphodiesterase Isoenzymes: Potential Targets for NovelAnti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBCTechnical Services Ltd, 1989). Studies carried out on this enzyme showthat its inhibition yields not only airway smooth muscle relaxation, butalso mastocyte suppression, basophil and neutrophil degranulation, thusinhibiting monocyte activation and neutrophil activation. Furthermore,the PDE 4 inhibitors activity is markedly improved when the adenylatedcyclase activity of the target cells is enhanced by endogenous hormones,as the case in vivo. Thus, PDE 4 inhibitors should be effective in thetherapy of asthma. Such compounds would offer a unique approach to thetherapy of various respiratory diseases both of allergic origin and not,and possess significant therapeutic advantages over the current therapy.

The excessive or irregular production of the tumor necrosis factor(hereinafter TNF_(α)), a cytokine with pro-inflammatory activityproduced by various kind of cells, affects the mediation or theexacerbation of many pathologies such as, for example, the adultrespiratory disease syndrome (ARDS) and the chronic pulmonaryinflammatory disease. Therefore, compounds able to control the negativeeffects of TNF_(α), i.e. the inhibitors of this cytokine, are to beconsidered useful against many pathologies.

The patent application EP-0 722 936 (in the name of Eisai) claims, interalia, compounds of formula

wherein n=0-4; R₁, is an optionally substituted lower alkoxy orcycloalkyl, or a —OR₉ group wherein R₉ is an optionally substitutedarylalkyl group; Y is —CB═ wherein B is an optionally substitutedheteroarylalkyl group or —NR₇R₈ wherein one of R₇, and R₈ may be H andthe other an optionally substituted heteroarylalkyl group; A is hydrogenor a halogen atom, optionally mono- or bi-substituted amino group,optionally substituted aryl, heteroaryl or heteroarylalkyl group. Amongthe groups optionally substituting the above mentioned residues halogenatoms are listed. Such compounds are said to be active as cGMP-PDEinhibitors, i.e. PDE 5, a phosphodiesterase acting by a cGMP-dependentmechanism and whose field of action is markedly cardiovascular (SchudtC. et al., Phosphodiesterase Inhibitors, Academic Press).

The patent application EP0 498 723 (in the name of Roussel Uclaf)discloses, inter alia, compounds of formula

wherein R₂b and R₃b are hydrogen, hydroxy, alkyl, cycloalkyl, acyloxy,at least one but no more then two of A₁b, A₂b, A₃b and A₄b are anitrogen atom and at least one of them is a methyne radical substitutedby the —R₅—Y_(B) group wherein R₅ is a divalent alkylene radical, andY_(B) represents the radical —Y_(1B)—B—Y_(2B) wherein Y_(1B) is amonocyclic aryl optionally containing nitrogen, B is a single bond andY_(2B) is hydrogen or halogen. These compounds are said to be effectivefor the treatment of arterial hypertension, heart and renal failure andfor the prevention of restenosis after angioplasty.

The patent application EP-0 017 411 (in the name of Pfizer) claimsphthalazines of formula

wherein R₁ is lower alkyl; Y is —(CH₂)_(m)—Z wherein m is 1 or 2, and Zis carbamoyloxy, carbonylamino, sulfamoyl, ureido, amino-sulfamoyl,carboxamino substituted on the terminal portion by a (C₃₋₇)cycloalkyl.These compounds are said to be phosphodiesterase inhibitors and to havea cardiac muscle stimulating activity, thus their action does not relateto PDE 4. The U.S. Pat. No. 3,274,185 (in the name of Messengill)describes, inter alia, phthalazines of formula

wherein Y and Y₁ are lower alkoxy; Z is phenyl optionally substituted byhalogen or benzyl; and R is hydrogen. These phthalazines are endowedwith sedative and hypertensive activity, without an explicit mechanismof action.

The U.S. Pat. No. 3,813,384 (in the name of Asta-Werke) illustrates,inter alia, benzylphthalazinones of formula

wherein R₁ and R₂ are lower alkoxy or halogen; X is an optionallybranched alkylene chain; m and n are 1-3; p is 0 or 1; and the

group is a C₃₋₈ mono-, bi- or tricyclic residue containing one or twonitrogen atom(s). Such compounds have a hystaminolytic action and areuseful, for example, in the treatment of asthma.

The patent application NL 8005411 (in the name of Mitsubishi Yuka)describes phthalazines of formula

wherein X is O or NH, R₁, R₂ and R₃ are, inter alia, (C₁₋₅)alkyl,(C₁₋₅)alkoxy, halogen or CF₃; n, m and p are 0-3. The use of thesecompounds is as platelet aggregation inhibitors.

The patent application JP-56061365 (in the name of Showa Denko)describes phthalazinones of formula

wherein, inter alia, R is halogen and n is 1-3, as vasodilators andanti-ulcer agents.

The patent application WO 97/40020 (in the name of Schering AG)illustrates, inter alia, compounds of formula

wherein R₁ and R₂ are H, nitro, halogen, amino, lower alkoxy or —CF₃; R₄is H or lower alkyl; R₅ is lower alkyl. These compounds areuncompetitive antagonists of excitatory aminoacids. The patentapplication WO097/48697 (in the name of Rhone Poulenc Rorer), publishedon Dec. 24, 1997, disloses, inter alia, compounds of formula

wherein A is an azaheterocycle and B an azaheteroaryl ring or anoptionally halo-substituted benzene ring; Z¹ is a bond or an oxygenatom; R¹ is H or lower alkyl optionally substituted by halogen atom(s);A¹ is a bond or a C₁₋₆ alkylene optionally substituted by aryl,cycloalkyl or heteroaryl; R² may be H, aryl heteroaryl; R³ may be aryl,heteroaryl, aryl-methoxy, heteroaryl-methoxy; n and m are alternatively0 or 1. The aryl and heteroaryl moieties may be substituted by halogenatoms. These compounds are PDE 4 and TNF inhibitors.

Therefore the present invention relates to compounds of formula I

wherein B is methylene, ethylene, amino, CONH or a bond;

Cy is phenyl or a 5- or 6-membered heterocycle containing from 1 to 3nitrogen atom(s), being both the residues optionally substituted by oneor more substituent(s);

R is H, phenyl or a (C₁₋₄)alkyl group optionally substituted by anaromatic or hydrogenated ring containing from 5 to 7 members;

R₁ is a (C₁₋₆)alkyl or polyfluoro(C₁₋₆)alkyl group;

R₂ is aryl aryl-(C₁₋₁₀)alkyl or a (C₄₋₇)cycloalkyl group optionallycontaining an oxygen atom and optionally substituted by a polarsubstituent;

and the N→O derivatives and pharmaceutically acceptable salts thereof;

with the proviso that when R is H, R₂ is not aryl-methyl.

The proviso is due to avoid the overlap with the patent applicationWO97/48697 (in the name of Rhone Poulenc Rorer) said above.

The compounds of formula I may have an asymmetric centre and thus may bein the form of stereoisomers. The objects of the present invention arethe compounds of formula I in the form of stereoisomeric mixtures aswell as single stereoisomers.

The compounds of formula I are active as PDE 4 and TNF_(α) inhibitors,and are thus used as therapeutic agents in allergic and inflammatorypathologies such as, for example, emphysema, chronic bronchitis, asthmaand allergic rhinitis.

As for 5- or 6-membered heterocycle it is meant pyrrole, imidazole,pyrazole, pyrrolidine, pyrroline, imidazoline, imidazolidine,pymzolidine, pyrazoline, pyridine, pyrazine, pyrimidine, pyridazine,piperazine, piperidine, triazine, and the like, preferably pyridine andpiperidine. The substituents optionally present on Cy may be keto,nitro, carboxy, halogen, this term embracing a fluorine, chlorine,bromine or iodine atom, chlorine being the preferred substituent.

Specific examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-ethyl-propyl,3-ethyl-utyl, 3-ethyl-tyl, n-exyl and the like. As for (C₅₋₇) cycloalkylgroup it is meant cyclopentyl, cyclohexyl and cycloheptyl, and when itcontains an oxygen atom it is meant, for example, tetrahydrofuran ortetrahydropyran, while aryl and aryl-(C₁₋₁₀) mean a ring or a C₆₋₁₀aromatic system such as, for example, phenyl, benzyl, phenethyl,phenyl-pentyl, naphthyl, indanyl, indanyl-pentyl and the like. For“polar substituent” it is meant those groups constituted by atoms withdifferent electronegativity thereby a dipole is created, such as, forexample, hydroxy or keto groups, are meant.

The N→O groups optionally preset in number of one or more may regardboth the nitrogen atoms of the phthalazine ring, and the ones on thesubstituent Cy.

Pharmaceutically acceptable salts of the compounds of formula I arethose with organic and inorganic acids, such as, for example,hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric,acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic,methansulfonic, 3,7-di-tert.butylnaphthalen-1,5-disulfonic (dibudinicacid).

Preferred compounds of formula I are those wherein B is methylene oramino; Cy is phenyl or a 5- or 6membered heterocycle containing from 1to 3 nitrogen atom(s), both the residues being optionally substituted by1 or 2 halogen(s); R is H, phenyl or a (C₁₋₄)alkyl group optionallysubstituted by an aromatic or hydrogenated ring containing 5-7 members;R₁ is a (C₁₋₆)alkyl or polyfluoro(C₁₋₆)alkyl group; R₂ is a(C₄₋₇)cycloalkyl group optionally containing an oxygen atom andoptionally substituted by a polar substituent; and the N→O derivativesand pharmaceutically acceptable salts thereof.

More preferred compounds of formula I are those wherein B is methylene;Cy is phenyl or a 6-membered heterocycle containing 1 nitrogen atom,being both the residue substituted by 1 or 2 chlorine atom(s); R isphenyl or a (C₁₋₄)alkyl group optionally substituted by a 5-7 membersaromatic or hydrogenated ring; R₁ is a (C₁₋₆)alkyl,polyfluoro(C₁₋₆)-alkyl group; R₂ is a (C₄₋₇)-cycloalkyl group optionallycontaining an oxygen atom and optionally substituted by a polarsubstituent; and the N→O derivatives and the pharmaceutically acceptablesalts thereof.

The synthesis of the compounds of formula I proceeds according tomethods known to the skilled in the art. For example, a benzaldehyde offormula II

wherein R₁ and R₂ are as defined above, is oxidized, for example withpotassium permanganate and tetrabutylammonitun bromide, to give an acidof formula III

wherein R₁ and R₂ are as defined above, which, for example by treatmentwith thionyl chloride, is turned into the corresponding acyl halide offormula IV

wherein R₁ and R₂ are as defined above and X is chlorine or bromine.This compound is reacted with diethylamine in an at least equimolaramount to give a benzamide of formula V

wherein R₁ and R₂ are as defined, which reacted with dimethylformamidein the presence of a strong organic base such as, for example,n-butyl-lithium, tert butyl-lithium, sec-butyl-lithium, optionally inthe presence of a binding agent such as, for example,tetramethylethylendiamine, yields a compound of formula VIa

wherein R₁ and R₂ are as defined above, and R¹ is hydrogen.

When a compound of formula I wherein R=H is desired, the compound offormula VIa is reacted with an equimolar amount of tert-butylcarbazoleto give a compound of formula VIIa

wherein R¹, R₁ and R₂ are as defined above, and R′ is a protecting groupof the carboxy moiety such as, for example, tert-butyl.

Instead, when a compound of formula I wherein R is other than hydrogenis desired, the compound of formula VIa is treated with R^(II)-magnesiumhalide, for example, chloride, or R^(II)-lithium, wherein R^(II) isphenyl or a (C₁₋₄)alkyl group optionally substituted by an aromatic orhydrogenated ring having from 5 to 7 members, to give a compound offormula XIII

wherein R^(II), R₁ and R₂ are as defined above. The compound of formulaXIII is treated with a suitable oxidising agent such as, for example,pyridinium-chloro chromate, and yields a compound of formula VIb

wherein R₁, R₂ and R^(II) are as defined above, which is treated with anequimolar amount of tert.butylcarbazole to give a compound of formulaVIIb, which differs from the compound VIIa in that R has the meanings offormula I but hydrogen.

The compound of formula VIIa or VIIb is reacted with trifluoroaceticacid to give the phthalazinone of formula VIII

wherein R, R₁ and R₂ are as defined above. This phthalazinone is reactedwith a halogenating agent such as, for example, phosphoryl chloride, togive the phthalazine of formula IX

wherein R, R₁ and R₂ are as defined above, and X′ is a halogen atom.

Alternatively, the compound of formula VIII may be directly obtainedfrom the compound of formula VIa or VIb by treatment with hydrazine inacetic acid.

The compound of formula IX yields a compound of formula I by treatmentwith a compound of formula XIV

Cy—B′—Y  (XIV)

wherein Cy is as defined above, B′ is methylene, ethylene, amino or abond and Y is hydrogen, halogen.

When a compound of formula I wherein B is CONH is desired, the compoundIX is reacted with carbon monoxide and methanol in the presence of acatalyst such as metal palladium or nickel, to give a compound offormula XV

wherein R, R₁, and R₂ are as defined above, which is then turned intothe desired compound of formula I through methods known to those skilledin the art, for example by reaction with an aryl-amine in the presenceof bases.

Alternatively, the compounds of formula I may be synthesized bytreatment of a compound of formula VIa or VIb with acetic acid in acidicmedium to give a compound of formula X

wherein R and R₁ are as defined above, and R′₂ has the meaning of R₂listed above plus hydrogen, which is reacted with hydrazine to give aphthalazinone of formula XI

wherein R, R₁ and R′₂ are as defined above. When R′₂ is hydrogen thiscompound is treated with the due compound of formula XIIa or XIIb

R₂OSO₂CH₃  (XIIa)

R₂X  (XIIb)

wherein R₂ and X are as defined above to give a compound of formula VIIIas described above.

Another alternative is for the compounds of formula I wherein B is otherthan amino, which may be yielded starting from the acid of formula IIIreacted with formaldehyde/HCl which forms a compound of formula XVI

wherein R₁ and R₂ are as defined above. This compound is oxidized, forexample with benzoyl peroxide/N-bromo-succinimide, then hydrolyzed togive a compound of formula XVII

wherein R₁ and R₂ are as defined above, which with a halogenidric acidand triphenylphosphine gives a compound of formula XVIII

wherein R₁ and R₂ are as defined above, which treated with an aldehydeof formula XIX

Cy—B″—CHO  (XIX)

wherein Cy is as defined above and B″ is methylene or is absent, in thepresence of an organic base such as, for example, triethylamine, gives acompound of formula XX

wherein R₁, R₂, B″ and Cy are as defined above. This is reacted withhydrazine to give a compound of formula XXI

wherein R₁, R₂, and Cy are as defined above and B is other than amino,which is treated with a halogenating agent, such as phosphoryl chlorideor bromide, to give a compound of formula XXII

wherein R₁, R₂, X and Cy are as defined above and B is other than amino.This compound is subjected to a coupling reaction with the suitablemetallorganic derivative in the presence of a catalyst, for example, apalladium-based catalyst, or to a nucleophilic substitution which givesa compound of formula I wherein B is other than amino.

A choice for having a compound of formula I wherein R₁ is apolyfluoro(C₁₋₆)alkyl group consists in treating a compound of formulaXXIII

wherein R′₁, is hydrogen, with bases, for example a carbonate orbicarbonate, and a polyfluoro(C₁₋₆)alkyl-chloride, -bromide or -iodideat 70-75° C. The compound of formula XXIII may be obtained from acompound of formula I wherein R₁ is (C₁₋₆)alkyl for example by treatmentwith sodium p-thiochresolate in the presence of a base such asdimethylformamide.

The synthesis of the N-oxides of the compounds of formula I is effectedby treating the compounds of formula I with peracids such as, forexample m-chloroperbenzoic acid.

The preparation of the salts of the compounds of formula I is effectedby conventional methods.

The compounds of formula I are PDE 4 inhibitors as resultant from the invitro enzymatic inhibition activity tests (Example 67), without anyeffect on PDE 3 and PDE 5 (Example 69). Moreover they are able toinhibit the TNF_(α) release (Example 68). Companions with the followingcompounds have been carried out:6,7-dimethoxy-4-(pyridin-4-yl-methyl)-2H-phthalazin-1-one (reference 1)and 6,7-dimethoxy-4-(piperidin-4yl-methyl)-2H-phthalazin-1-one(reference 2) embraced by the general formula of the patent applicationEP-0 722 936 (in the name of Eisai) just cited above, chosen in view ofthe structural affinity with the compounds of the invention. Thereference compounds, though chemically alike, did not show to be activeon PDE 4.

It is apparent how these receptorial selectivity and specificityfeatures joined with the lack of activity on the cardiovascular systemmake the compounds of formula I particularly suitable for the treatmentof the pathologies involving PDE 4 and TNF_(α) even if in the presentcontext the interest is specifically focused on the respiratorypathologies. Especially the compounds of the invention are useful in thetreatment of allergic and inflammatory diseases and above all in thetherapy of emphysema, of chronic obstructive pulmonary disease andchronic bronchitis in particular, of asthma and allergic rhinitis.

The therapeutical dosage shall generally be comprised between 0.1 and1,000 mg a day and between 1 and 100 mg by oral route for a singleadministration.

A further object of the present invention are the pharmaceuticalcompositions comprising a therapeutically effective amount of thecompounds of formula I or of the pharmaceutically acceptable saltsthereof in admixture with a suitable carrier.

The pharmaceutical compositions object of the invention may be liquid,suitable for enteral or parenteral administration, and, preferably,solid such as tablets, capsules, granulates, suitable for oral admin on,or in a form suitable for the transdermic or inhalatory administration.The preparation of the pharmaceutical compositions object of theinvention may be effected according to common techniques.

Provided below are examples in order to better illustrate the presentinvention.

EXAMPLE 1 Synthesis of 3-Cyclopentyoxy-4-methoxy Benzoic Acid

A solution of potassium permanganate (53.1 g, 0.336 moles) in water (1l) was added under stirring with a solution of bromidetetrabutylamnonium (111.68 g, 0.336 moles) in water (0.4 l). The formedsolid was isolated by filtration, washed with water and dissolved inpyridine (0.5 l). The solution was dropped into a solution of crude3-cyclopentyloxy-4-methoxy benzaldehyde (obtained as described in J.Med. Chem., 1995, 38, page 4851) (74 g, 0.336 moles) in pyridine (0.2 l)under stign water/ice. At the end ice (3 l) was added and the whole wasacidified by dropping 12N HCl (0.85 l). The stirng was kept on for 1.5hours more, then the solid was isolated by filtration and extraced underftiing for 30 minutes in ethyl acetate (2 l). The solid residue wasremoved and the mother liquor was further extracted in ethyl acetate(2×0.7 l). The organic phases were washed with water, anhydrified oversodium sulfate and brought to a small volume to give 53.2 g of the titleproduct (yield: 67%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.75-6.87 (m, 3H); 4.87-4.79 (m, 1H);3.90 (s, 3H); 2.08-1.52 (m, 8H).

EXAMPLE 2 Synthesis of 3-Cyclopentyloxy-4-methoxy Benzoic Acid Chloride

A solution of 3-cyclopentyloxy-4-methoxy benzoic acid (53 g, 0.224moles) obtained as described in example 1, in thionyl chloride (200 ml)was refluxed for 2 hours under nitrogen, then evaporated to dryness andtaken up twice in toluene (100 ml) to give 57 g of the title productwhich was used as such in the next step.

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.81-7.72 (dd, 1H); 7.52-7.50 (d, 1H);6.91-6.85 (d, 1H); 4.87-4.75 (m, 1H); 3.91 (s, 3H); 2.08-1.50 (m, 8H).

EXAMPLE 3 Synthesis of 3-Cyclopentyloxy-N,N-diethyl-4-methoxy-benzamide

A solution of 3-cyclopentyloxy-4-methoxy benzoic acid chloride (57 g,0.224 moles) obtained as described in example 2, in methylene chloride(250 ml) was dropwise added at 5-10° C. with diethylamine (69.2 g, 0.672moles). The mixture was evaporated to dryness, dissolved in ethylacetate, washed with water, 2% potassium bisulfate, water again andsodium bicarbonate, anhydrified over sodium sulfite and dried. Theresidue was taken up in petrolatum (250 ml) to give 61.2 g of the titleproduct (yield: 94%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 6.94-6.78 (m, 3H); 4.80-4.70 (m, 1H);3.82 (s, 3H); 3.50-3.22 (m, 4H); 1.98-1.50 (m, 8H); 1.17 (t broad, 6H).

EXAMPLE 4 Synthesis of3-Cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide and5-Cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide

A solution of 3-cyclopentyloxy N,N-diethyl-4-methoxy-benzamide (61.2 g,0.21 moles), obtained as described in example 3, andterramethylethylendiaiuine (34.86 ml, 0.231 moles) in drytetrahydrofuran (480 ml) was dropwise added under stirring at −75° C.with sec-butyl-lithium (195.76 ml, 0.231 moles) and, after 1 hour at thesame temperature, with dimethylformamide (53.66 ml, 0.693 moles). Aftera further half hour at −75° C., the reaction mixture was poured into aphosphate buffer pH=7, ethyl acetate and concentrated HCl. Theextraction was repeated twice with fresh ethyl acetate, then the extractwas washed with 5% potassium bisulfate, then with water, thenanhydrified over sodium sulfate and dried, the residue waschromatographed over silica gel (eluent petrolatum/ethyl acetate 1:1) togive 23.3 g of the first title product (product A; yield: 35%) and 6.7 gof the second title product (product B: yield: 10%).

Product A: ¹H-NMR (200 MHz, CDCl₃) δ (PPM): 10.44 (s, 1H); 7.09-6.85 (m.2H); 5.05-4.98 (m, 1H); 3.84 (s, 3H); 3.59-3.47 and 3.05-2.92 (2q, 4H);1.95-1.52 (m, 8H); 1.28 and 0.95 (2t, 6H). Product B: ¹H-NMR (200 MHz,CDCl₃) δ (PPM): 9.86 (s, 1H); 7.3 (s, 1H); 6.73 (s, 1H); 4.87-4.76 (m,1H); 3.88 (s, 3H); 3.58 and 3.12 (2q, 4H); 2.05-1.52 (m, 8H); 1.26 and1.02 (2t, 6H).

EXAMPLE 5 Synthesis ofN′-(2-Cyclopentyloxy-6-diethylcarbamoyl-3-methoxy-benzylidene)-hydrazincarboxyAcid tert-Butyl Ester

A solution of 3-cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide(21.7 g, 0.068 moles) obtained as described in example 4, product A, andtert-butylcarbazole (12.84 g, 0.1 moles) in absolute ethanol (217 ml)was refluxed for 3 hours, then dried, taken up in petrolatum and driedagain. The residue was taken up in ethyl ether (100 ml) and petrolatum(0.2 l), then filtered and the mother liquor was dried to give 27.45 gof the title product (yield: 93%). ¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.60(m, 1H); 8.05 (s broad, 1H); 6.87 (s, 2H); 4.87-4.72 (m, 1H); 3.82 (s,3H); 3.58-3.25 (m, 4H); 190-150 (m, 8H); 1.40 (s, 9H); 1.22-1.06 (2t,6H).

EXAMPLE 6 Synthesis of 5-Cyclopentyloxy-6-methoxy-2H-phthalazin-1-one

Trifluoroacetic acid (150 ml) was added withN′-(2-cyclopentyloxy-6-diethylcarbamoyl-3-methoxy-benzylidene)-hydrazincarboxyacid tert-butyl ester (27.35 g, 0.063 moles) obtained as described inexample 5, under stirring at 5-10° C., then the mixture was stirred for15 minutes and dried. The residue was dissolved in methylene chloride(750 ml) and left at room temperature for 6 hours, then washed with 5%sodium bicarbonate to alkalinity, then with water, anhydrified oversodium sulfate and dried. The residue was taken up in ethyl ether (0.11)and filtered to give 15.58 g of the title product (yield: 95%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 10.12 (m, 1H); 8.84 (s, 2H); 8.11 and7.36 (2d, 2H); 5.11-5.01 (m, 1H); 3.98 (s, 3H); 2.00-1.60 (m, 8H).

EXAMPLE 7 Synthesis of5-Cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine

A slurry under nitrogen of5-cyclopentyloxy-6-methoxy-2H-phthalazin-1-one (7.5 g, 28.81 mmoles),obtained as described in example 6, in phosphoryl chloride (30 ml) washeated under stirring to 80° C., then concentrated to dryness, and theresidue was dissolved in ethyl acetate and washed with potassiumbicarbonate to alkalinity, then with water, anhydrified over sodiumsulfate and evaporated to dryness to give 7.95 g of the tide product(yield: 99%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.40 (s, 2H); 8.11 and 7.36 (2d, 2H);5.11-5.01 (m, 1H); 3.98 (s, 3H); 2.00-1.60 (m, 8H).

EXAMPLE 8 Synthesis of5-Cyclopentyloxy-1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-phthalazine(Compound 1)

A solution of 3,5-dichloro-4-methyl-pyridine (13.86 g, 85.56 mmoles) indry dimethylformamide (100 ml) was added, under nitrogen and stirring,with 55% NaH (3.73 g, 85.56 mmoles). The mixture was stirred for 1 hourthen added with a solution of5-cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine (7.95 g, 28.52mmoles), obtained as described in example 7, in dry dimethylfomamide (70ml). The mixture was left to stand for one night, quenched with water,diluted with water and extracted methyl aceate. The extract was washedwith water and anhydrified over Na₂SO₄, then evaporated to dryness. Theresidue was flash chromatographed (eluent:petrolatum/ethyl acetate 1:1)to give 6.58 g of the title product (yield: 57%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.92 (s, 1H); 8.49 (s, 2H); 7.89 (d,1H, JHH=9.1 Hz); 7.63 (d, 1H); 5.21-5.14 (m, 1H); 4.86 (s, 2H); 4.03 (s,3H); 1.98-1.57 (m, 8H).

EXAMPLE 9 Synthesis of5-Cyclopentyloxy-1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-phthalazin-3-oxide(Compound 2)

A solution under stirring of5-cyclopentyloxy-1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-phthalazine(0.1 g, 0.741 mmoles), obtained as described in example 8, in methylenechloride (2 ml), was added with 55% m-chloroperbenzoic acid (255.75 mg,0.816 mmoles). The mixture was diluted with methylene chloride, washedwith a solution of NaHCO₃, anhydrified and dried. The residue was flashchromatographed over silica gel (eluent:methylene chloride/ethyl acetate1:1) and the eluate taken up in ether to give 0.2 g of the title product(yield: 64%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.64 (s, 1H); 8.50 (s, 2H); 7.82 (d,1H, JHH=9 Hz); 7.40 (d, 1H); 5.16-5.09 (m, 1H); 4.79 (s, 2H); 4.02 (s,3H); 1.92-1.55 (m, 8H).

EXAMPLE 10 Synthesis of5-Cyclopentyloxy-1-(3,5-dichloropyridin-4-yl-methyl)-6-hydroxy-phthalazine

A solution under nitrogen of5-cyclopentyloxy-1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-phthalazine(1.2 g, 2.97 mmoles), obtained as described in example 8, and sodiump-thiochresolate (866 mg, 5.94 mmoles) in dimethylformamide (20 ml), washeated to 90-95° C. for 2 hours. The reaction mixture was left to standfor 1 night, poured into water/ice, filtered, and the precipitate wassuspended in 95° ethanol (30 ml) and stirred for 0.5 hour. The resultingsolid was separated by filtration, dissolved by refluxing inmethanol/chloroform 1:1 (100 ml) and concentrated to small volume togive 410 mg of the title product which were used as such in the nextstep.

¹H-NMR (200 MHz, DMSO) δ (ppm): 10.89 (m, 1H); 9.42 (s, 1H); 8.66 (s,2H): 8.09 and 7.69 (dd, 2H, JHH=8.9 Hz); 5.23-5.17 (m, 1H); 4.89 (s,2H); 1.87-1.56 (m, 8H).

EXAMPLE 11 Synthesis of5-Cyclopentyloxy-1-(3,5-dichloropyridin-4-yl-methyl)-6-difluoromethoxy-phthalazine(Compound 3)

In a solution of5-cyclopentyloxy-1-(3,5dichloropyridin-4-ylmethyl)6hydroxy-phthalazine(400 mg, 1.025 mmoles), obtained as described in example 10, potassiumcarbonate (188.4 mg, 1.366 mmoles) and potassium iodide (68.3 mg) indimethylformamide (20 ml), a stream of chloro difluoro mane was gurgledby heating at 70-75° C. under stirring. After 4.5 hours, the mixture waspoured into water, extracted m ethyl acetate, the extract was washedwith water, anhydrified over sodium sulfate and dried. The residue waschromatographed on silica gel (eluent:petrolatum/ethyl acetate 7:3) togive an oil which was crystallized from ethyl ether/40-60° petrolatum1:3 to give 96 mg of the title product (yield: 21%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.68 (s, 1H); 8.52 (s, 2H); 7.90 and7.82 (dd, 2H, JHH=9 Hz); 6.66 (t, H, JHF=73.5 Hz); 5.17-5.10 (m, 1H);4.90 (s, 2H); 2.02-1.62 (m, 8H).

EXAMPLE 12 Synthesis of5-Cyclopentyloxy-1-(3,5-dichloropyridin-4-ylamino)-6-methoxy-phthalazine(Compound 4)

A solution of 2,5-dichloro-4-amino-pyridine (5.1 g, 31.4 mmoles) in drydimethylformamide (100 ml) under nitrogen was added under stirring with55% sodium hydride (1.37 g, 31.4 mmoles). The mixture was stirred for 1hour, then dropwise added with a solution of5-cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine (1.75 g, 6.28 mmoles)in dry dimethylformamide (20 ml) and the mixture was heated to 100° C.for 2 hours. The whole was poured into water and extracted in ethylacetate. The e was washed with water and anhydrified over sodiumsulfate, tend dried. The residue was taken up in few of methylenechloride, the insoluble was filtered off and the solution dried, theresidue was purified by silica gel chromatography (eluent:methylenechloride+1% of methanol) and the crude was chromatographed a second time(eluent:petrolatum/ethyl acetate 7:3) to give 720 mg of the tide product(yield: 22%)

¹H-NMR (200 MHz CDCl₃) δ (ppm): 9.59 (m, 1H); 8.32 (s, 2H); 8.28 (s,1H); 8.23 and 7.33 (2d, 2H, JHH=8.9 Hz); 5.11-5.03 (m, 1H); 3.98 (s,3H); 1.96-1.57 (m, 8H).

EXAMPLE 13 Synthesis of 3-Benzyloxy-4-methoxy Benzoic Acid

A solution of potassium permanganate (24.81 g, 0.157 moles) in water(0.1 l) was added under stirring with a solution of tetrabutylammoniumbromide (50.61 g, 0.157 moles) in water (0.2 l). The formed solid wasseparated by filtration, washed with water, squeezed, then dissolved inpyridine (0.3 l). The solution was dropped into a solution of3-benzyloxy-4-methoxy benzaldehyde (38.2 g, 0.157 moles) in pyridine(0.15 l) in water bath. After 3 hours the reaction mixture was broughtto acidic pH by 1N HCl, the solid was filtered off and the mother liquorextracted more times in methylene chloride. The organic phases wereanhydrified and concentrated to dryness and the residue taken up with 1NNaOH and washed with ethyl ether. The aqueous solution was acidified andextracted twice with methylene chloride, brought to dryness, discolouredwith TONSIL® and concentrated to small volume. The resulting precipitatewas filtered to give 35.869 g of the title product (yield: 88%)

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.78-6.69 (m, 8H); 5.18 (s, 2H); 3.39(s, 3H).

EXAMPLE 14 Synthesis of 3-Benzyloxy-4-methoxy Benzoic Acid Chloride

Operating analogously to example 2 starting from 3-benzyloxy-4-methoxybenzoic acid (35.86 g, 0.139 moles) obtained as described in example 1,in thionyl chloride (150 ml), 35.01 g of the title product were obtained(yield: 98%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.84-6.90 (m, 8H); 5.16 (s, 2H); 3.95(s, 3H).

EXAMPLE 15 Synthesis of 3-Benzyloxy-N,N-diethyl-4-methoxy-benzamide

Operating analogously to example 3 starting from 3-benzyloxy-4-methoxybenzoic acid chloride (35.01 g, 0.127 moles) obtained as described inexample 14, in methylene chloride (200 ml), and diethylamine (131 ml,92.54 g, 0.127 moles) in methylene chloride (130 ml), 37.65 g of thetitle product were obtained (yield: 95%)

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.43-6.84 (m, 8H); 5.14 (s, 2H); 3.88(s, 3H): 3.31 (m, 4H); 1.07 (m, 6H).

EXAMPLE 16 Synthesis of3-Benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide

A solution of 3-benzyloxy-N,N-diethyl-4-methoxy-benzamide (39.54 g,126.2 mmoles) obtained as described in example 15, andtetramethylethylendiamine (16.13 g, 138.3 mmoles) in tetrahydrofuran(4.25 l), cooled to −78° C., was dropwise added with 1.21Ms-butyl-lithium (115.64 ml, 138.8 mmoles). After 2 hours N,Ndimethylfomamide was added (43 ml, 40.59 g, 555 mmoles) and the mixturewas left at the same temperature for 4 hours, then 1 night while thetemperature arose. The mixture was washed with 0.47M phosphate bufferpH=7 and the organic phases were separated, the aqueous one wasextracted in ethyl ether. The organic phases were anhydrified andconcentrated to give a solid which was filtered off. The mother liquorwas dried and the crude flash chromatographed (eluent:ethylacetate/petrolatum 1:1) to give 13.76 g of the title product (yield:32%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 10.22 (s, 1H); 7.36-7.29 (m, 5H); 7.13and 6.94 (2s, 2H, JHH=8.3 Hz); 5.17 (s, 2H); 3.94 (s, 3H); 3.52 and 2.93(2q, 4H); 1.26 and 0.93 (2t, 6H).

EXAMPLE 17 Synthesis of 3,4-Dihydroxy-5-methoxy-3H-isobenzofuran-1-one

3-Benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (11.6 g, 34 mmoles)obtained as described in example 16 was dissolved in 10% HCl and aceticacid (80+80 ml) and the mixture was refluxed for 18 hours. The solventswere evaporated and the crude was taken up in toluene. The solid waswashed with ethyl ether and dried to give 6.66 g of the title product(quantitative yield).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.64 add 7.82 (2s broad, 2H); 7.28-7.16(m, 2H); 3.89 (s, 3H); 6.53 (s broad, 1H).

EXAMPLE 18 Synthesis of 5-Hydroxy-6-methoxy-2H-phthalazin-1-one

3,4-Dihydroxy-5-methoxy-3H-isobenzofuran-1-one (6.63 g, 34 mmoles)obtained as described in example 17 was dissolved in ethanol (60 ml) andadded with 98% hydrazine (8.5 ml). The mixture was heated untillimpidity and after 5 minutes the formed precipitate was filtered,treated with 1N HCl. The mother liquor was concentrated more times andthe fractions of solid obtained were joined to give 4.65 g of the titleproduct (yield: 72%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 12.33 (m, 1H); 10.06 (s, 1H); 8.36 (s,1H); 7.68 and 7.49 (2d, 2H, JHH=8.6 Hz); 3.94 (s, 3H).

EXAMPLE 19 Synthesis of Methansulfonic Acid 2,3-Dihydro-1H-inden-2-ylEster

2-Indanol (5.14 g, 38.3 mmoles) in methylene chloride (20 ml) at 0° C.was added with triethylamine (6.13 ml 4.46 g, 44.1 mmoles) and asolution of mesyl chloride (3.26 ml, 4.83 g, 42.1 mmoles) in methylenechloride (4 ml). The temperature was raised to room value, then themixture was poured into water and the organic phase separated, washedwith water, anhydrified and dried to give 8.12 g of the title product(yield: 99%)

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.27-7.16 (m, 4H); 5.55-5.46 (m, 1H);3.42-3.18 (m, 4H); 3.00 (s, 3H).

EXAMPLE 20 Synthesis of 5-(Indan-2-yloxy)-6-methoxy-2H-phthalazin-1-one

Methansulfonic acid 2,3-dihydro-1H-inden-2-yl ester (3.31 g, 15.61mmoles) obtained as described in example 19, in dimethylformamide (12ml) was treated with Na₂CO₃ (2.21 g, 20.32 mmoles) and KI in catalyticamount at 90° C. After 1 night at this temperature5-hydroxy-6-methoxy-2H-phthalazin-1-one (2 g, 10.41 mmoles) obtained asdescribed in example 18 was added and the mixture was left at 90° C. foranother night, then poured into 1N HCl, and the precipitate wasfiltered, tritured in petrolatum and dried to give 2.55 g of the titleproduct (yield: 80%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 12.43 (s, 1H); 7.97 and 7.64 (2d, 2H,JHH=8.8 Hz); 7.72 (s, 1H); 7.30-7.16 (m, 4H); 5.42-5.34 (m, 1H); 3.99(s, 3H); 3.22-2.99 (m, 4H).

EXAMPLE 21 Synthesis of1-Chloro-5-(indan-2-yloxy)-6-methoxy-2H-phthalazine

5-(Indan-2-yloxy)-6-methoxy-2H-phthalazin-1-one (2.55 g, 8.3 mmoles)obtained as described in example 20, was suspended, under nitrogen, inphosphoryl chloride (20 ml). The reaction mixture was refluxed for 1hour then poured into diluted NaOH (pH=8), extracted in methylenechloride, anhydrified and dried. The crude was tritured in petrolatum togive 2.57 g of the title product (yield: 95%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.20 (s, 1H); 8.02 and 7.65 (2d, 2H,JHH=8.8 Hz); 7.27-7.17 (m, 4H); 5.58-5.50 (m, 1H); 4.07 (s, 3H); 3.18(m, 4H).

EXAMPLE 22 Synthesis of1-(3,5-Dichloro-pyridin-4-methyl)5-(indan-2-yloxy)-6-methoxy-2H-phthalazine(Compound 5)

A solution of 3,5-dichloro-4-methyl-pyridine (3.63 g, 22.4 mmoles) indimethylformamide (50 ml) was added under stirring with 55% sodiumhydride (0.977 g, 67.2 mmoles), then with a solution of1-chloro-5-(indan-2-yloxy-6-methoxy-2H-phthalazine (2.44 g, 7.5 mmoles)obtained as described in example 21, in dimethylformamide. Afterstirring for 1.5 hours the mixture was poured into a buffer at pH=7 andextracted in methylene chloride. The extract was washed with water,anhydrified and evaporated to dryness. The residue was flashchromatographed (eluent petrolatum/ethyl aceate 6:4) to give 1.7 g ofthe title product (yield: 54%).

1H-NMR (200 MHz, CDCl₃) δ (ppm): 9.31 (s, 1H); 8.49 (s, 2H); 7.94 and7.68 (2d, 2H, JHH=9.1 Hz); 7.27-7.16 (m, 4R); 5.57-5.47 (m, 1H); 4.87(s, 2H); 4.07 (s, 3H); 3.23-3.20 (m, 4H).

EXAMPLE 23 Synthesis of Methansulfonic Acid 5-Phenyl-pentyl Ester

Operating analogously to example 19 using 5-phenylpentanol (7.18 ml, 7g, 42.6 mmoles) in methylene chloride (8 ml) and methyl-sulfonylchloride (3.63 ml, 5.37 g, 46.9 mmoles) in methylene chloride (4 ml),and also using triethylamine (6.82 ml, 4.96 g, 49 mmoles) to adjust thepH after the addition of methyl-sulfonyl chloride, 10.57 g of the titleproduct were obtained after half an hour of reaction (stoichiometricyield).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.31-7.13 (m, 5H); 4.20 (t, 2H, JHH=6.5Hz); 2.96 (s, 3H); 2.65-2.57 (m, 2H); 1.83-1.34 (m, 6H).

EXAMPLE 24 Synthesis of 5-(5-Phenyl-pentyl-1-oxy)-6-methoxy-2H-phthalazin-1-one

Operating analogously to example 20 using5-hydroxy-6-methoxy-2H-phthalazin-1-one 2 g, 10.41 mmoles) obtained asdescribed in example 18, sodium carbonate (2.21 g, 20.82 mmoles),potassium iodide in catalytic amount, methansulfonic acid5-phenyl-pentyl ester (3.78 g, 15.61 mmoles) obtained as described inexample 23, and dimethylformamide (50 ml) under nitrogen, 3.11 g of thetide product were obtained (yield: 88%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 10.19 (s broad, 1H); 8.41 (s, 1H); 8.13and 7.35 (2d, 2H, JHH=8.8 Hz); 7.30-7.11 (m, 5H); 4.11 (t, 2H, JHH=6.6Hz); 3.96 (s, 3H); 2.68-2.60 (m, 2H); 1.91-1.45 (m, 6H).

EXAMPLE 25 Synthesis of1-Chloro-5-(5-phenyl-pentyl-1-oxy)-6-methoxy-phthalazine

Operating analogously to example 21, using5-(5-phenyl-pentyl-1-oxy)-6-methoxy-2H-phthalazin-1-one (3.05 g, 9.01mmoles), obtained as described in example 24, and phosphoryl chloride (5ml) the title product was obtained as a crude which was used as such inthe next step.

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.66 (s, 1H); 8.01 and 7.63 (2d, 2H,JHH=9 Hz); 7.30-7.12 (m, 5H); 4.20 (t, 2H, JHH=6.6 Hz); 4.02 (s, 3H);2.68-2.60 (m, 2H); 1.94-1.47 (m, 6H).

EXAMPLE 26 Synthesis of1-(3,5-Dichloro-pyridin-4-methyl)-5-(5-phenyl-pentyl-1-oxy)-6-methoxy-phthalazine(Compound 6)

Operating analogously to example 22 and using1-chloro-5-(5-phenyl-pentyl-1-oxy)-6-methoxy-phthalazine (3.2 g, 9.01mmoles) obtained as described in example 25,3,5dichloro-4-methyl-pyridine (4.38 g, 27.03 mmoles), 55% sodium hydride(1.18 g) and dimethylformamide (50 ml), 0.6 g of the title product wasobtained.

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.68 (s, 1H); 8.51 (s, 2H); 8.93 and7.65 (2d, 2H, JHH=9.2 Hz); 7.30-7.12 (m, 5H); 4.88 (s, 2H); 4.21 (t, 2H,JHH=6.6 Hz); 4.03 (s, 3H); 2.68-2.61 (m, 2H); 1.96-1.47 (m, 6H).

EXAMPLE 27 Synthesis of 7-Cyclopentyloxy-6-methoxy-2H-phthalazin-1-one

Operating analogously to example 6 starting from7-cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (obtainedsimilarly to the compound of example 4) the title product was obtained(yield: 80%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 10.90 (s, 1H); 8.03 (s, 1H); 7.72 (s,1H); 7.00 (s, 1H); 4.96 (m, 1H); 3.98 (s, 3H); 2-18-1.60 (m, 8H).

EXAMPLE 28 Synthesis of7-Cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine

Operating analogously to example 7 starting from7-cyclopentyloxy-6-methoxy-2H-phthalazin-1-one, obtained as described inexample 27, the tide product was obtained (yield: 98%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.21 (s, 1H); 7.42 (s, 1H); 7.13 (s,1H); 5.00 (m, 1H); 4.02 (s, 3H); 2.20-1.60 (m, 8H).

EXAMPLE 29

cl Synthesis of7-Cyclopentyloxy-1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-phthalazine(Compound 7)

Operating analogously to example 8 using7-cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine, obtained asdescribed in example 28, the title product was obtained (yield: 59%).

¹H-NMR (200 MHz CDCl₃) δ (ppm): 9.20 (s, 1H); 8.49 (s, 2H); 7.28 (s,1H); 7.14 (s, 1H); 4.97 (m, 1H); 4.83 (s, 2H); 4.02 (s, 3H); 2.18-1.60(m, 8H).

EXAMPLE 30 Synthesis of7-Cyclopentyloxy-1-(3,5-dichloropyridin-4-ylamino)-6-methoxy-phthalazine(Compound 8)

Operating analogously to example 12 using7-cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine, obtained asdescribed in example 28, the title product was obtained (yield: 28%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.40 (s broad, 1H); 8.36 (s, 2H); 7.90(s, 1H); 7.83 (s, 1H); 6.95 (s, 1H), 3.00 (m, 1H); 3.98 (s, 3H);2.20-1.50 (m, 8H).

EXAMPLE 31 Synthesis ofN,N-Diethyl-5-cyclopentyloxy-2-(1-hydroxyethyl)-4-methoxybenzamide

A solution of 5-cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide(3.2 g, 10 mmoles), obtained as described in example 4, product B, indry tetrahydrofuran (50 ml) at 0° C., was dropwise added with a 3Msolution of methyl-magnesium chloride (4 ml, 12 moles) intetrahydrofuran. The mixture was stirred at room temperature for 1 hour,then carefully poured into a mixture of ethyl aceate (0.1 l) and water(0.2 l) and cooled to 3° C. The organic phase was washed with water,anhydrified over Na₂SO₄ and dried at reduced pressure to give a residuewhich was chromatographed on silica gel (eluent:ethyl acetate/hexane1:1) to give 2.7 g of the title product (yield: 80%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.40 (s, 1H); 6.82 (s, 1H); 5.41 (q,1H); 4.86 (m, 1H); 4.01 (q, 2H); 3.93 (s, 3H); 3.55 (q, 2H); 2.18-1.70(m, 8H); 1.58 (d, 3H); 1.40-1.10 (m, 6H).

EXAMPLE 32 Synthesis ofN,N-Diethyl-5-cyclopentyloxy-2-(1-hydroxypropyl)-4methoxy-benzamide

Operating analogously to example 31 using5-cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide, obtained asdescribed in example 4, product B, and ethyl-magnesium bromide the titleproduct was obtained (yield 76%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.53 (s, 1H); 6.81 (s, 1H); 5.43 (t,1H); 4.85 (m, 1H); 4.08 (q, 2H); 3.95 (s, 3H); 3.75 (q, 2H); 2.33 (m,2H); 2.20-1.60 (m, 8H); 1.51-1.10 (m, 9H).

EXAMPLE 33 Synthesis ofN,N-Diethyl-5-cyclopentloxy-4-methoxy-2-(1-oxoethyl)-benzamide

A solution ofN,N-diethyl-5-cyclopentyloxy-2(1-hydroxyethyl)-4-methoxybenzamide (2 g,6 mmoles) obtained as described in example 31, in CH₂Cl₂ (25 ml) at 10°C. was added with pyridinium-chloro-chromate (1.9 g, 9 mmoles), and themixture was stirred at room temperature for 1 night, then added withethyl ether (50 ml) and the residue was washed with ethyl ether (30 ml).The joined solutions were evaporated at reduced pressure and the residuechromatographed on silica gel (eluent:hexane/ethyl acetate 6:4) to give1.5 g of the title product (yield: 77%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.6 (s, 1H); 6.87 (s, 1H); 4.9 (m, 1H);4.1 (q, 2H); 4 (s, 3H); 3.76 (q, 2H); 2.5 (s, 3H); 2.2-1.6 (m, 8H);1.4-1.1 (m, 6H).

EXAMPLE 34 Synthesis ofN,N-Diethyl-5-cyclopentyloxy-4-methoxy-2-(1-oxopropyl)-benzamide

Operating analogously to example 33 starting fromN,N-diethyl-5-cyclopentyloxy-2-(1-hydroxypropyl)-4-methoxy-benzamide,obtained as described in example 32, the title product was obtained(yield: 82%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.58 (s, 1H); 6.85 (s, 1H); 4.85 (m,1H); 4.15 (q, 2H); 3.96 (s, 3H); 3.74 (q, 2H); 3.42 (q, 2H); 2.20-1.60(m, 8H); 1.53 (t, 3H); 1.40-1.10 (m, 6H).

EXAMPLE 35 Synthesis of7-Cyclopentyloxy-4-methyl-6-methoxy-2H-phthalazin-1-one

Operating analogously to example 6 usingN,N-diethyl-5-cyclopentyloxy-4-methoxy-2-(1-oxoethyl)-benzamide obtainedas described in example 33, the title product was obtained.

EXAMPLE 36 Synthesis of7-cyclopentyloxy-4-ethyl-6-methoxy-2H-phthalazin-1-one

Operating analogously to example 6 using fromN,N-diethyl-5-cyclopentyloxy-4-methoxy-2-(1-oxopropyl)-benzamide,obtained as described in example 34, the title product was obtained.

EXAMPLE 37 Synthesis of1-Chloro-7-cyclopentyloxy-4-methyl-6-methoxy-phthalazine

Operating analogously to example 7 starting from7-cyclopentyloxy-4-methyl-6-methoxy-2H-phthalazin-1-one, obtained asdescribed in example 35, the tide product was obtained.

EXAMPLE 38 Synthesis of1-Chloro-7-cyclopentyloxy-4-ethyl-6-methoxy-phthalazine

Operating analogously to example 7 starting from7-cyclopentyloxy-4-ethyl-6-methoxy-2H-phthalazin-1-one, obtained asdescribed in example 36, the title product was obtained.

EXAMPLE 39 Synthesis of7-Cyclopentyloxy-1-(3,5-dichloro-pyridin-4-ylmethyl)-4-methyl-6-methoxy-phthalazine(Compound 9)

Operating analogously to example 8 starting from1-chloro-7-cyclopentyloxy-4-methyl-6-methoxy-phthalazine, obtained asdescribed in example 37, the title product was obtained.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 8.50 (s, 2H); 7.30 (s, 1H); 7.23 (s,1H); 5.04-5.00 (m, 1H); 4.82 (s, 2H); 4.05 (s, 3H); 2.88 (s, 3H);2.10-1.81 (m, 6H); 1.80-1.60 (m, 2H).

EXAMPLE 40 Synthesis of7-Cyclopentyloxy-1-(3,5-dichloro-pyridin-4-ylmethyl)-4-ethyl-6-methoxy-phthalazine(Compound 10)

Operating analogously to example 8 using1-chloro-7-cyclopentyloxy-4-ethyl-6-methoxy-phthalazine, obtained asdescribed in example 38, the tide product was obtained.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 8.50 (s, 2H); 7.32 (s, 1H); 7.29 (s,1H); 5.01-5.05 (m, 1H); 4.81 (s, 2H); 4.05 (s, 3H); 3.26 (q, 2H, J=7.5Hz); 2.13-1.67 (m, 8H); 1.48 (t, 3H, J=7.5 Hz).

EXAMPLE 41 Synthesis of Methansulfonic Acid Tetrahydro-pyran-2-ylmethylEster

A solution of (tetrahydropyran-2-yl)methanol (6 g, 51.65 moles) inmethylene chloride (80 ml) at 0° C. was added with triethylamine (8.27ml, 59.4 moles) then with mesyl chloride (4.4 ml, 56.8 moles) inmethylene chloride (5 ml). The temperature was left to rise to roomvalue and after 30 minutes the mixture was poured into water andextracted in methylene chloride. The organic phases were anhydrified anddried to give 10 g of the title product (quantitative yield).

EXAMPLE 42 Synthesis of6-Methoxy-5-(tetrahydro-pyran-2-yl-methoxy)-2H-phthalazin-1-one

A solution of 5-hydroxy-6-methoxy-2H-phthalazin-1-one (1.5 g, 7.81mmoles), obtained as described in example 18, in dimethylformamide (40ml) was added with Na₂CO₃ (1.65 g, 15.61 mmoles) and KI in catalyticamount and the mixture was heated to 90° C. in nitrogen atmosphere. Asolution of methansulfonic acid tetrahydropyran-2-ylmethyl ester (6.1 g,31.46 mmoles), obtained as described in example 41, in dimethylformamide(14 ml) was dropped therein. After 24 hours the mixture was poured intowater and thrice extracted in ethyl acetate. The organic phases werewashed with water till neutrality then anhydrified and concentratedunder vacuum to give a solid which tritured in ethyl ether yielded 1.66g of the title product (yield: 66%)

EXAMPLE 43 Synthesis of1-Chloro-6-methoxy-5-(tetrahydro-pyran-2-yl-methoxy)-phthalazine

Operating analogously to example 7 staring from6-methoxy-5-(tetrahydropyran-2-yl-methoxy)-2H-phthalazin-1-one (1.48 g,5.12 mmoles), obtained as described in example 42, and phosphorylchloride (6 ml) 1.65 g of the title product as a crude were obtained andused as such in the next step.

EXAMPLE 44 Synthesis of1(3,5-Dichloropyridin-4-yl-methoxy-5-(tetrahydro-pyran-2-yl-methoxy)-phthalazine(Compound 11)

Operating analogously to example 8 using1-chloro-6-methoxy-5-(tetrahydropyran-2-yl-methoxy-phthalazine, obtainedas described in example 43, in dimethylformamide, 55% NaH and3,5-dichloro-4-methyl-pyridine in dimethylformamide, the title productwas obtained (yield: 35%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 9.77 (s, 1H); 8.50 (s, 2H); 7.91 (d,1H, JHH=9.0 Hz); 7.62 (d, 1H); 4.86 (s, 2H); 4.18-4.05 (m, 2H);4.06-3.42 (m, 3H); 4.04 (s, 3H); 1.94-1.38 (m, 6H).

EXAMPLE 45 Synthesis of1-(3,5-Dichloropyridin-4-yl-methyl)-6-methoxy-5-(tetrahydro-pyran-2-yl-methoxy)-phthalazin-3-oxide(Compound 12)

Operating analogously to example 9 starting from1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-5-(tetrahydropyran-2-yl-methoxy)-phthalazine(0.2 g, 0.48 mmoles) obtained as described in example 44, in methylenechloride (2 ml) and m-chloroperbenzoic acid (0.143 g, 0.58 mmoles) 0.104g of the tide product was obtained (yield: 48%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.82 (s, 1H); 8.50 (s, 2H); 7.84 (d,1H, JHH=9.0 Hz); 7.39 (d, 1H); 4.78 (s, 2H); 4.13-3.98 (m, 3H); 4.02 (s,3H); 3.74-3.41 (m, 2H); 1.91-1.35 (m, 6H).

EXAMPLE 46 Synthesis of Methansulfonic Acid Tetrahydro-furan-3-yl Ester

A solution of tetrahydrofuran-3-ol (4.6 g, 52.2 moles) in methylenechloride (70 ml) at 0° C. was added with triethylamine (8.36 ml, 60moles) and mesyl chloride (4.44 ml, 57.4 moles) in methylene chloride(85 ml). The temperature was left to rise to room value and after 1 hourthe mixture was poured into water and in methylene chloride. The organicphases were anhydrified and dried to give 8.12 g of the title product(yield: 93%).

EXAMPLE 47 Synthesis of6-Methoxy-5-tetrahydro-furan-3-yloxy)-2H-phthalazin-1-one

Operating analogously to example 42 using5-hydroxy-6-methoxy-2H-phthalazin-1-one (1.55 g, 8.07 mmoles) obtainedas described in example 18, in dimethylformamide (35 ml), sodiumcarbonate (1.71 g, 16.13 mmoles), potassium iodide in catalytic amountand methansulfonic acid tetrahydrofuran-3-yl ester (2.01 g, 12.1 mmoles)obtained as described in example 46, in dimethylformamide (10 ml), 0.73g of the tide product was obtained (yield: 86%).

EXAMPLE 48 Synthesis of1-Chloro-6-methoxy-5-(tetrahydro-furan-3-yloxy)-phthalazine

Operating analogously to example 7 starting from6-methoxy-5-(tetrahydro-furan-3-yloxy)-2H-phthalazin-1-one (1.73 g, 6.6mmoles) and phosphoryl chloride (6.7 ml, 73 mmoles), 1.63 g of the titleproduct were obtained (yield: 88%).

EXAMPLE 49 Synthesis of1-(3,5-Dichloropyridin)-4-ylmethy)-6-methoxy-5-(tetrahydrofuran-3-yloxy)-phthalazine(Compound 13)

Operating analogously to example 8 starting from3,5-dichloro-4-methyl-pyridine (2.47 g, 16.89 mmoles), sodium hydride(0.74 g, 16.89 mmoles),1-chloro-6-methoxy-5-(tetrahydrofuran-3-yloxy)-phthalazine (1.58 g, 5.63mmoles) obtained as described in example 48, in dimethylformamide (35ml) 0.74 g of the title product (yield: 63%) were obtained.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 9.65 (s, 1H); 8.49 (s, 2H); 7.93 and7.65 (2d, 2H, JHH=9.0 Hz); 5.36-5.28 (m, 1H); 4.86 (s, 2H); 4.22-3.80(m, 4H); 4.05 (s, 3H); 2.32-2.00 (m, 4H).

EXAMPLE 50 Synthesis of1-(3,5-Dichloropyridin-4-ylmethyl)-6-methoxy-5-tetrahydrofuran-3-yloxy)-phthalazin-3-oxideand1-(3,5-Dichloro-1-oxy-pyridin-4-ylmethyl)-6-methoxy-5-(tetrahydrofuran-2-yloxy)-phthalazine3-Oxide (Compound 14 and 19) Operating analogously to example 9 startingfrom1-(3,5-dichloropyridin-4-ylmethyl)-methoxy-5-(tetrahydrofuran-3-yloxy)-phthalazine(0.74 g, 1.82 mmoles) obtained as described in example 49, in methylenechloride (4 ml) and m-chloroperbenzoic acid (0.72 g, 2.93 mmoles), 0.331g of the first title product was obtained. From the chromatographiccolumn 0.207 g of the second title product was eluted (eluent:methylenechloride/methanol 9:1)

First product: ¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.67 (s, 1H); 8.50 (s,2H); 7.86 and 7.41 (2d, 2H, JHH=8.9 Hz); 5.30-5.24 (m, 1H); 4.80 (s,2H); 4.15-3.76 (m, 4H); 4.04 (s, 3H); 2.26-2.00 (m, 4H).

Second product: ¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.68 (s, 1H); 8.19 (s,2H); 7.85 (d, 1H, JHH=9.1 Hz); 7.42 (d, 1H); 5.32-5.25 (m, 1H); 4.73 (s,2H); 4.05 (s, 3H); 4.16-3.76 (m, 4H); 2.20-2.00 (m, 2H.

EXAMPLE 51 Synthesis of6-Hydroxy-5-(tetrahydrofuran-2-yloxy)-2H-phthalazin-1-one

A solution of 6-methoxy-5-(tetrahydrofuran-2-yloxy)-2H-phthalazin-1-one(680 mg, 2.6 mmoles), obtained as described in example 47, in DMF (15ml) and sodium p-thiochresolate (378.6 mg, 2.6 mmoles) was heated to 90°C. for 10 hours, poured into water, acidified at pH 6-7 with 1M HCl,dried, take up in water and dried again. The crude was chromatographed(eluent:methylene chloride/methanol 9:1) to give 330 mg of the titleproduct (yield: 52%).

¹H-NMR (200MH, DMSO) δ (ppm): 12.41 (s, 1H); 11.07 (s-broad, 1H); 8.23(s, 1H); 7.82 (d, 1H, JHH=8.8 Hz); 7.44 (d, 1H); 5.25-5.20 (m, 1H);4.03-3.59 (m, 4H); 2.11-2.00 (m, 2H)

EXAMPLE 52 Synthesis of6-Difluoromethoxy-5-(tetrahydro-furan-2-yloxy)-2H-phthalazin-1-one

6-Hydroxy-5-(tetrahydrofuran-2-yloxy)-2H-phthalazin-1-one (320 mg, 1.29mmoles), obtained as described in example 51, in dry DMF (80 ml) andK₂CO₃ (267 mg, 1.93 mmoles) were treated with Freon-22 (5 g, 58 mmoles)at 0.5 bar. The mixture was brought to 115° C. for 1 night, then driedand chromatographed (eluent:benzene/ethyl acetate 1:1, then ethylacetate only) to give 300 mg of the title product (yield: 78%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 10.62 (s, 1H); 8.44 (s, 1H); 8.16 (d,1H, JHH=9.2 Hz); 7.55 (d, 1H); 6.63 (t, 1H, 3H=72 Hz); 5.24-5.18 (m,1H); 4.18-3.75 (m, 4H); 2.29-2.09 (m, 2H).

EXAMPLE 53 Synthesis of1-Chloro-6-difluoromethoxy-5-(tetrahydro-furan-2-yloxy)-phthalazine

A solution of6-difluoromethoxy-5-(tetrahydrofuran-2-yloxy)-2H-phthalazin-1-one (280mg, 0.94 mmoles), obtained as described in example 52, and POCl₃ (1.2ml) was heated to 90° C. for 1.5 hours, then dried, taken up inmethylene chloride, washed with a saturated solution of NaHCO₃, thentwice with water, anhydrified and dried to give 296 g of the titleproduct (yield: 99.7%).

EXAMPLE 54 Synthesis of1-(3,5-Dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-5-(tetrahydro-furan-3-yloxy)-phthalazine(Compound 15)

A solution under nitrogen of 3,5-dichloro-4-methyl-pyridine (457 mg,2.82 mmoles) in dry DMF (10 ml) was portionwise added with 60% NaH (113mg, 2.82 mmoles) and, after 1 hour at room temperature, was dropwiseadded, at a temperature <10° C., with1-chloro-6-difluoromethoxy-5-(tetrahydrofuran-2-yloxy)-phthalazine (296mg, 0.937 mmoles), obtained as described in example 53, in dry DMF (10ml). After 2 hours at room temperature the mixture was poured into a0.4M buffer at pH=7 (50 ml), extracted in ethyl acetate (2×50 ml) andthe organic phase was washed with water, anhydrified and concentratedunder vacuum. The residue was chromatographed (eluent:benzene/ethylacetate 1:1, then ethyl acetate only), then crystallized from ethylether/benzene to give 180 mg of the title product (yield: 43.5%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.72 (s, 2H); 8.52 (s, 2H); 7.96 (d,1H, JHH=9.2 Hz); 7.80 (d, 1H); 6.68 (t, 1H, JHF=74 Hz); 5.34-5.29 (m,1H); 4.91 (s, 2H); 4.22-3.81 (m, 4H); 2H).

EXAMPLE 55 Synthesis of1-(3,5-Dichloro-pyridin-4-ylmethy-6-difluoromethoxy-5-(tetrahydro-furan-3-yl-oxy)-phthalazine3-oxide and1-(3,5-dichloro-1-oxy-pyridin-4-ylmethyl)-6-difluoromethoxy-5-tetrahydro-furan-3-yloxy)-phthalazine3-oxide (Compound 16 and 17)

A solution of1(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-5-(tetrahydro-furan-3-yloxy)-phthalazine(1.5 g, 3.39 mmoles) in methylene chloride (20 ml) and 55%m-chloroperbenzoic acid (1.56 g, 4.99 mmoles) was kept under nitrogenfor 2 hours at room temperature.

The mixture was evaporated to dryness, taken up in water, neutralizedwith NaHCO₃, extracted in ethyl acetate, anhydrified and dried. Thecrude oil was chromatographed (eluent:ethyl acetate, then ethylacetate/methanol 7:3), then tritured in petrolatum/ethyl ether 8:2,filtered, washed with petrolatum and dried under vacuum to give 0.5 g ofthe first title product (yield: 32.25%) and 0.6 g of the second titleproduct (yield: 37.33%).

First product: ¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.67 (m, 1H); 8.47 s,2H); 7.86 (d, 1H, JHH=9.2 Hz); 7.53 (d, 1H); 6.69 (t, 1H, JHF=72 Hz);5.29-5.23 (m, 1H); 4.80§, 2H); 4.13-3.75 (m, 4H); 2.23-2.11 (m, 2H).

Second product: ¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.68 (m, 1H); 8.19§,2H); 7.84 (d, 1H, JHH=9.2 Hz); 7.54 (d, 1H); 6.68 (t, 1H, JHF=72 Hz);5.30-5.25 (m, 1H); 4.75§, 2H); 4.15-3.76 (m, 4H); 2.24-2.16 (m, 2H).

EXAMPLE 56 Synthesis of[1,4-bis(Diphenylphosphino(butane]-dichloropalladium(II)

A solution of PdCl₂(CH₃CN)₂ (405 mg, 1.561 mmoles) in benzene undernitrogen and magnetic stirring was added with1,4-diphenylphosphanyl)butane (665 mg, 1.561 mmoles). After 1.5 hours aprecipitate formed and was added with hexane (10 ml), filtered, washedwith hexane and dried under vacuum to give 620 mg of the tide product(66%).

EXAMPLE 57 Synthesis of6-Methoxy-1-phenyl-5-tetrahydro-furan-2-yloxy)-phthalazine (Compound 18)

A suspension of magnesium (0.078 g, 3.21 mmoles) in tetrahydrofuran (1ml) was dropwise added, under nitrogen and stirring with a solution of1,2-dibromoethane (0.3 g, 1.6 mmoles), 3-bromo-pyridine (0.25 g, 1.6mmoles) in tetrahydrofuran (1 ml). 30 Minutes after the end of thedropping a solution of ZnCl₂ (0.22 g, 1.6 mmoles) in tetrahydrofuran (3ml) was added. After 20 minutes[1,4-bis(diphenylphosphino(butane]-dichloropalladium(II) (0.016 g, 0.026mmole), obtained as described in example 57, and1-chloro-6-methoxy-5-(tetrahydro-furan-3-yloxy)-phthalazine (0.15 g,0.53 mmole) obtained as described in example 48, were added and themixture was refluxed for 1.5 hours, then cooled, washed with water andextracted in ethyl acetate. The organic phase was anhydrified and dried.The aqueous phase was evaporated and taken up in ethyl acetate. Thejoined organic phases were dried and the residue flash chromatographed(eluent:methylene chloride/methanol 9:1) to give 0.071 g of the titleproduct.

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 9.79 (s, 1H); 8.96-7.35 (m, 4H);7.77-7.54 (m, 2H); 5.37-5.32 (m, 1H); 4.24-3.80 (m, 6H); 4.02 (s, 3H);2.34-2.01 (m, 2H).

EXAMPLE 58 Synthesis of 5,6-Dimethoxy-3H-isobenzofuran-1-one

Under mechanical stirring a slurry of 3,4-dimethoxybenzoic acid (353.5g, 1.94 moles) in HCHO (1.71, 24.5 moles) was prepared and cooled inice, saturated with gaseous HCl (340 g, 9.32 moles), then graduallybrought to 60° C. After 1 night the temperature was brought to roomvalue and further HCl (300 g) was gurgled therein, then the temperaturewas brought to 60° C. again overnight. The mixture was brought to smallvolume, taken up in water (1 l), neutralized with 28% NH₄OH (1.5 l) andkept at cold for 2 hours, then filtered. The filtrate was washed withwater till neutrality, then crystallized from methanol (2 l) and driedunder vacuum at 60° C. to give 220 g of the title product (yield:58.65%).

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 7.28 and 6.28 (2s, 2H); 5.20 (s, 2H);3.95 and 3.91 (2s, 6H).

EXAMPLE 59 Synthesis of 2-Formyl-4,5-dimethoxy-benzoic Acid

A mixture under nitrogen of 5,6-dimethoxy-3H-isobenzofuran-1-one (10 g,51.5 mmoles), obtained as described in example 58, in carbontetrachloride (250 ml), N-bromo-succinimide (13.88 g, 77.25 mmoles) andbenzoyl peroxide (320 mg, 1.23 mmoles) was refluxed for 2 hours, thencooled, filtered and washed with a solution of 10% Na₂SO₃ (200 ml), thenwith water, anhydrified and dried. The residue was taken up in 5% HCl(100 ml) and refluxed for 4 hours, then the solution was cooled,alkalinized with NaOH, washed with ethyl acetate and slowly acidified togive a precipitate which was filtered, washed with water and dried overP₂O₅ under vacuum to give 6.43 g of the title product (yield: 60%).

EXAMPLE 60 Synthesis of5,6-Dimethoxy-3-(triphenyl-λ⁶-phosphanyl)-3H-isobenzofuran-1-one

A slurry under nitrogen of 2-formyl-4,5dimethoxy-benzoic acid (6.43 g,30.62 mmoles), obtained as described in example 59, triphenyl-phosphine(8.3 g, 30.62 mmoles), HBr in 30% acetic acid (8.26 ml, 30.62 mmoles)and glacial acetic acid (20 ml) was heated to 90° C. for 4.5 hours. Themixture was dried, dissolved in acetonitrile (50 ml) and diluted withethyl ether till slurry, then cooled and filtered, and the filtrate waswashed with ethyl ether and dried under vacuum to give 13.6 g of thetitle product (yield: 83%).

¹H-NMR (200 MHz, DMSO) δ (ppm): 8.35 and 7.31 (2s, 2H); 8.03-7.66 (m,15H); 6.01 (s, 1H); 3.84 and 3.45 (2s, 6H).

EXAMPLE 61 Synthesis of5,6-Dimethoxy-3-pyridin-4-ylmethylen-3H-isobenzofuran-1-one

In a slurry of5,6-dimethoxy-3-triphenyl-λ⁶-phosphanyl)-3H-isobenzofuran-1-one (78 g,145 mmoles), obtained as described in example 60, and4-pyridincarboxaldehyde (13 ml, 145 mmoles) in methylene chloride (1 l),triethylamine (20 ml, 145 mmoles) was dropped at room temperature understirring. After 1.5 hours the mixture was filtered and dried and theresidue treated with ethanol at reflux, cooled and filtered. The motherliquor was chromatographed (eluent:methylene chloride then with 1% ofmethanol) and the residue dried and joined with the filtrate above togive 25 g of the title product.

EXAMPLE 62 Synthesis of6,7-Dimethoxy-4-pyridin-4-ilmethyl-2H-phthalazin-1-one

5,6-Dimethoxy-3-pyridin-4-ylmethylen-3H-isobenzofuran-1-one (25 g, 88.34mmoles), obtained as described in example 61, was reacted with hydratehydrazine (500 ml) for 2 hours at room temperature under stirring, thenfor 1 hour at reflux. The mixture was diluted with water (300 ml),cooled and filtered to give 23 g of the tide product (yield: 87%).

EXAMPLE 63 Synthesis of1-Chloro-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine

A slurry of 6,7-dimethoxy-4-pyridin-4-ylmethyl-2H-phthalazin-1-one (10g, 33.6 mmoles), obtained as described in example 62, in POCl₃ (70 ml)was heated to 90° C. for 4 hours. POCl₃ was evaporated and the residuedissolved in water, a saturated solution of NaHCO₃ and NaOH till theformation of a precipitate which was filtered and suspended in methanol,dried, suspended in acetone and filtered again. The residue was dried at45° C. under vacuum to give 9.56 g of the title product.

EXAMPLE 64 Synthesis of1-Benzyl-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine (Compound 20)

In anhydrous environment, ZnCl₂ (863 mg, 6.33 mmoles) was dissolved intetrahydrofuran (20 ml), and a 2M solution of benzyl magnesium chloridein tetrahydrofuran (3.2 ml, 2.5 equivalents) was dropped therein. After30 minutes 1-chloro-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine (800mg, 2.53 mmoles), obtained as described in example 63, palladium acetate(71 mg, 0.316 mmole) and triphenylphosphine (166 mg, 0.633 mmole) wereadded and the whole was refluxed. After 1 hour the mixture was pouredinto a saturated solution of NH₄Cl and by adding ethyl acetate a solidprecipitated. The whole was evaporated to dryness and the residue takenup in methylene chloride and extracted with concentrated ammonia. Theorganic phase was dried to yield a residue which was chromatographed(eluent:methylene chloride/2% methanol, then methylene chloride/5%methanol). The oily eluate was dissolved in methylene chloride and byadding HCl/ethyl ether a precipitate formed which was tritured in ethylacetate and filtered to give 788 mg of the title product (yield: 64.8%).

¹H-NMR (200 MHz, DMSO) δ (ppm): 8.89-8.06 (m, 4H); 7.96 and 7.86 (2,2H); 7.54-7.19 (m, 5H); 5.23 and 5.04 (2s, 4H); 4.08 and 4.03 (2s, 6H).

EXAMPLE 65 Synthesis of1-Bromo-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine

6,7-Dimethoxy-4-pyridin-4-ylmethyl-2H-phthalazin-1-one (5 g, 16.8mmoles), obtained as described in example 62, was suspended inacetonitrile (30 ml) and added with POBr₃ (14.5 g, 50.4 mmoles). Moreacetonitrile was added (total 65 ml) and the mixture was heated to 70°C. for 16 hours. More POBr₃ (8.1 g) was added and the heating kept onfor 7 hours. The solid was filtered off and the mother liquor pouredinto 1N KOH and extracted with ethyl acetate. The filtrate was slowlyput in KOH and extracted with CH₂Cl₂. The organic extracts were joined,anhydrified over Na₂SO₄ and the solvent evaporated. The residue wascrystallized from CH₂Cl₂, and the mother liquor was dissolved inmethylene chloride/1% methanol and chromatographed (eluent:methylenechloride/2% methanol then methylene chloride/3% methanol). Joining thecrystallized and the eluate 1.89 g of the title product were obtained(yield: 31%).

EXAMPLE 66 Synthesis of6,7-Dimethoxy-1-phenyl-4-pyridin-4-ylmethyl-phthalazine (Compound 21)

In dry environment, ZnCl₂ (379 mg, 2.78 mmoles) was dissolved intetrahydrofuran (20 ml), then the temperature was brought to 0° C. and a2M solution of phenyl lithium in hexane (1.4 ml, 2.8 mmoles) was droppedtherein. The temperature was left to rise to room value and1-bromo-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine (500 mg, 1.39mmoles), obtained as described in example 65, palladium acetate (15 mg,0.0695 mmole) and triphenylphosphine (36 mg, 0.139 mmole) were added andthe whole was refluxed for 1.5 hour. The reaction was stopped with somedrops of NaOH, then the mixture was dried and the residue taken up inwater and CH₂Cl₂. The organic phase was dried to yield a residue whichwas chromatographed (eluent:methylene chloride, then methylenechloride/2% methanol, then methylene chloride/5% methanol). The eluatewas dissolved in methylene chloride, treated with TONSIL® and filteredover celite. The mother liquor was dried yielding 172 mg of the titleproduct.

¹H-NMR (200 MHz, DMSO) δ (ppm): 8.83-7.96 (m, 4H) 7.85-7.64 (m, 5H);7.82 (s, 1H); 7.37 (s, 1H); 5.00 (s, 2H); 4.07 and 3.89 (2s, 6H).

EXAMPLE 67 PDE 4 Enzyme Inhibition Test

a) Purification of Human Polymorphonucleate Leukocytes

The polymorphonucleate leukocytes (PMNs) were isolated from peripheralblood of healthy volunteers according to what described by Boyum A,Scand. J. Immunol., 1976, 5° suppl., 9). Shortly, the isolation of thePMNs was effected by Ficoll-Paque gradient centrifugation followed bysedimentation on dextrane and the erythrocyte contamination waseliminated by hypotonic lysis.

b) PDE 4 Enzyme Purification

The human PMNs were resuspended in TRIS/HCl buffer (10 mM pH 7.8)containing MgCl₂ (5mM), EGTA (4 mM), mercaptoethanol (5 mM), TRITON-X100(1%), pepstatin A (1 μM), PMSF (100 μM) and leupeptin (1 μM), andhomogenised by Polytron. The homogenate was centrifuged at 25,000×g for30 minutes at 4° C. and the surnatant was used for the PDE 4 enzymepurification by ion exchange chromatography using the FPLC techniqueaccording to what described by Schudt C. et al., Naunyn-Schmidberg'sArch. Pharmacol., 1991, 334, 682. The surnatant was seeded on a UNO Q12column (Bio-Rad) and the enzyme was eluted by sodium acetate gradientfrom 50mM to 1M. The fractions containing enzymatic activity werejoined, dialysed against water and concentrated. The resulting PDE 4enzyme was stored at −20° C. in the presence of ethylenglycole (30%)v/v) until use.

c) PDE 4 Enzyme Inhibition

The enzyme activity was assessed with an Amersham kit based on the SPAtechnique (Scintillation Proximity Assay). The enzymatic reaction waseffected in a total volume of 100 μl of TRIS/HCl buffer (50 mM, pH7.5),MgCl₂ (8.3mM), EGTA (1.7 mM), cAMP (1μM) and [³H]cAMP (˜100.000 dpm).The compounds of the invention and the reference ones were added at thewanted concentrations. As reference compounds 6,7dimethoxy-4-(pyridin-4-ylmethyl)-2H-phthalazin-1 on (reference 1) and6,7-dimethoxy-4-(piperidin-4-ylmethyl)-2H-phthalazin-1-one (reference 2)embraced by the general formula of the patent application EP-0 722 936(in the name of Eisai) were used. The reaction was started by adding theenzyme (15 μg protein/ml) in 40 minutes at 30° C. and stopped with 50 μlof SPA particles suspension. The radioactivity of the particles wasmeasured in β-emitting counter. The IC₅₀ values were computed over 9equidistant concentrations in logarithmic scale using a 4-parameterslogistic function by a software. The results are set forth in Table 1.

TABLE 1 PDE 4% inhibition (M) Compound 10⁻⁵ 10⁻⁶ 10⁻⁸ IC₅₀ nM 1 84 1953.1 ± 10 2 97 94 25 42.4 ± 5 3 100 34 38.9 ± 7 4 73 58.9 ± 5 5 80 3329.5 ± 4 6 79 27 56.8 ± 9 7  186 ± 43 9  146 ± 38 10  93 80 33 74.9 ± 813   153 ± 85 14   298 ± 37 15   282 ± 36 19   206 ± 124 Reference1 >100 μM Reference 2 >100 μM

EXAMPLE 68 TNF₆₀ Inhibition Test

a) Human Monocytes Isolation

The monocytes were isolated from peripheral blood of healthy volunteersaccording the procedure of Schreek L., J. Natl. Cancer Inst., 1964, 32,507. The monocytes and lymphocytes population was isolated by Ficollgradient centrifugation, and the cells diluted at a density of 2.5×10⁶cells/ml in RPMI1640 incubation containing 1% inactivated bovine fetalserum, penicillin (100 U/ml) and streptomycin (100 U/ml) were placed in24-wells plates (1 ml/well) and left to adhere for 1 hour at 37° C. with5% CO₂. At the end of the incubation the lymphocytes not adhering wereremoved by aspiration and the monocytes adhered to the plate were usedin the next step.

b) TNF_(α) Synthesis Inhibition

The TNF_(α) synthesis from human monocytes was measured according to themethod of Barnette M. et al., Biochemical Pharmacology, 1996, 51, 949.The monocles were incubated for 1 hour with 1 ml of RPMI1640 incubationmedium (1% inactivated bovine serum, 100 U/ml penicillin andstreptomycin) containing different concentrations of the productsaccording to the present invention or the carrier only for the controls.The TNF_(α) synthesis from monocytes was induced by adding 1ng/ml of LPS(lipopolysaccharide of E. Coli) and after 16 hours of incubation at 37°C., 5% CO₂, the incubation medium was removed, and the surnatant storedat −80° C. until the measurement. The TNF_(α) levels were determined byELISA test with an Amersham kit. The results are set forth in Table 2 asIC₅₀ measured with the same calculation of example 67.

TABLE 2 Compound IC₅₀ nM 1  254 ± 84 2  139 ± 55 3  167 ± 79 4  187 ± 355  252 ± 120 6 83.5 ± 24 10  259 ± 86 14  389 ± 47

EXAMPLE 69 PDE 3 and 5 Enzymes Inhibition Test

a) Human Platelet Preparation

Human platelets were prepared from platelet rich plasma (PRP) obtainedfrom the Hematological Dept. of the “L.Sacco” Hospital of Milan. The PRPwas centrifuged at 2,200 rpm for 15 minutes at 4° C. and the pellet wassuspended in lysis solution (15 ml; 155 mM NH₄Cl, 10 mM KHCO₃ and 0.1 mMNa₂EDTA, pH=7.4) and incubated for 10 minutes on ice-bath to remove theerythrocyte contamination. After a centrifuging at 1,400 rpm for 10minutes at 4° C., platelets were suspended in 10 ml of 145 nM NaCl, 5 mMKCl, 1 mM MgSO₄, 10 mM glucose, 10 mM HEPES and 0.05 U/ml of hirudin(pH=7.4), and stored at −20° C. until homogenization and chromatography.

b) Purification of PDE 3 and PDE 5 with Fast Protein LiquidChromatography (FPLC)

Before the chromatographic step, platelets were thawed and 50 ml of 20mM TRIS (pH=6.5) containing 5 mM βmercapto-ethanol, 2 mM EDTA, 50mMsodium acetate and 50 μM PMSF (homogenization buffer) were added. Theplatelet suspension was then homogenized by a Polytron homogenizer(Polytron PT 1200) for 20 seconds. The homogenate was centrifuged at14,500 rpm for 20 minutes at 4° C., and the supernatant was applied to aUNO Q12 column (Bio-Rad) pre-equilibrated with the PMSF. A flow rate of4.5 ml/min was used throughout the ion exchange chromatographyprocedure. The column was washed with PMSF (180 ml) and PDE 3 and PDE 5were eluted by sodium acetate linear gradient from 0.05M to 1M. Thefractions containing enzymatic activity were joined, dialysed againstwater and concentrated 10 times by ultrafiltration. The resultingsolution was stored at −20° C. in the presence of ethylenglycole (30%)v/v) until use.

c) Assay of Phosphodiesterase Activity

The enzyme activity was assessed with an Amersham kit based on the SPAtechnique (Scintillation Proximity Assay). The enzymatic reaction waseffected in a total volume of 100 μl of TRIS/HCl buffer (50 mM, pH7.5),MgCl₂ (8.3 mM), EGTA (1.7 mM), cAMP (for PDE 3 assay) or cGMP (for PDE 5assay) (1 μM), [³H]cAMP or [³H]cGMP (10 μl), and and 10 μl of thecompounds of the invention. The reaction was started by adding theenzyme (10 μl) incubated for 40 minutes at 30° C. and stopped by adding50 μl of SPA beads. The radioactivity due to the particles was measuredin β-emitting counter. The results are expressed as percent activityversus the control present in each test.

TABLE 3 PDE 3 PDE 5 % inhibition % inhibition Compound at 10⁻⁶ M at 10⁻⁶M 1  0 20 2 20 4 3 5 14 4 8 19 6 25 20 10 20 20 13 4 2 15 11 0 19 — 8

What is claimed is:
 1. A compound of formula I

wherein G is methylene, ethylene, imino, CONH or a bond; Cy is phenyl ora 5- or 6-membered heterocycle of the group consisting of pyrrole,imidazole, pyrazole, pyrrolidine, pyrroline, imidazoline, imidazolidine,pyrazolidine, pyrazoline, pyridine, pyrazine, pyrimidine, pyridazine,piperazine, piperidine, and triazine, the Cy residue being optionallysubstituted by one or more substituent(s) selected from the groupconsisting of keto, nitro, carboxy, fluorine, chlorine, bromine, oriodine; R is H, phenyl or a (C₁₋₄)alkyl group optionally substituted byphenyl; R₁ is a (C₁₋₆)alkyl or polyfluoro(C₁₋₆)alkyl group; R₂ is aryl,aryl-(C₁₋₁₀)-alkyl, (C₄₋₇)cycloalkyl or (C₄₋₇)heterocycle wherein theheteroatom is an oxygen atom; and the derivatives of formula (I) inwhich one and/or the other of the nitrogens of the phthalazine centralnucleus as well as the nitrogens on the substituent Cy may be an N→Ooxide, or the pharmaceutically acceptable salts thereof; with theproviso that when R is H, R₂ is not aryl-methyl.
 2. A compound accordingto claim 1 wherein G is methylene or imino; Cy is phenyl or a 5- or6-membered heterocycle containing from 1 to 3 nitrogen atom(s), beingboth the residues substituted by one or two halogen(s); R is H, phenylor a (C₁₋₄)alkyl group optionally substituted by phenyl; R₁ is a(C₁₋₄)alkyl or polyfluoro(C₁₋₆)alkyl group; R₂ is a (C₄₋₇)cycloalkyl or(C₄₋₇)heterocycle wherein the heteroatom is an oxygen atom; andderivatives of formula (I) in which one and/or the other of thenitrogens of the phthalazine central nucleus may be an N→O oxide, or thepharmaceutically acceptable salts thereof.
 3. A compound according toclaim 1 wherein G is methylene; Cy is phenyl or a 6-membered heterocyclecontaining 1 nitrogen atom, being both the residues substituted by oneor two halogen(s); R is phenyl or a (C₁₋₄)alkyl group optionallysubstituted by phenyl ; R₁ is a (C₁₋₆)alkyl or polyfluoro(C₁₋₆)alkylgroup; R₂ is a (C₄₋₇)cycloalkyl or (C₄₋₇)heterocycle wherein theheteroatom is an oxygen atom; and derivatives of formula (I) in whichone and/or the other of the nitrogens of the phthalazine central nucleusmay be an N→O oxide, or the pharmaceutically acceptable salts thereof.4. A process for preparing a compound according to claim 1 wherein G ismethylene, ethylene, imino or a bond, characterized in that abenzaldehyde of formula II

wherein R₁ and R₂ are as defined in claim 1 is oxidised to give an acidof formula III

wherein R₁ and R₂ are as defined above, which is transformed into thecorresponding acyl halide of formula IV

wherein R₁ and R₂ are as defined above and X is chlorine or bromine:this compound is reacted with diethylamine to give a benzamide offormula V

wherein R₁ and R₂ are as defined above, which reacted withdimethylformamide in the presence of a strong base yields a compound offormula VIa

wherein R₁ and R₂ are as defined above, and R₁ is hydrogen, which, whena compound of formula I wherein R is hydrogen is desired, is reactedwith tert-butylcarbazole to give the compound of formula VIIa

wherein R¹, R₁ and R₂ are as defined above, and R′ is a protecting groupof the carboxy moiety; instead when a compound of formula I wherein R isother than hydrogen is desired, the compound of formula VIa is treatedwith a R^(II)-magnesium halide or R^(II)-lithium, wherein R^(II) isphenyl or a (C₁₋₄)alkyl group optionally substituted by an aromatic orhydrogenated ring having from 5 to 7 members, to give a compound offormula XIII

wherein R^(II), R₁ and R₂ are as defined above, which treated with asuitable oxidising agent, yields a compound of formula VIb

wherein R₁, R₂ and R^(II) are as defined above, which is treated withtert-butylcarbazole to give the compound of formula VHb, differing fromthe compound VIIa in that R has the meanings of formula I hydrogenexcluded; the compound of formula VIIa or VIIb is reacted withtriffuoroacetic acid to give the phthalazinone of formula VIII

wherein R, R₁ and R₂ are as defined above; this is reacted with ahalogenating agent to give the phthalazine of formula IX

wherein R, R₁ and R₂ are as defined above, and X′ is a halogen atom,which by treatment with a compound of formula XIV Cy-G′Y  (XIV) whereinCy is as defined in claim 1, G′ is methylene, ethylene, amino or a bondand Y is hydrogen or halogen, provides the desired compound.
 5. Apharmaceutical composition containing a therapeutically amount of acompound according to claim 1 in admixture with a suitable carrier.
 6. Acompound by the name of1-(3,5-dichloro-pyridin-4-methyl)-5-(indan-2-yloxy)-6-methoxy-2H-phthalazine.7. A compound by the name of1-(3,5-dichloro-pyridin-4-methyl)-5-(5-phenyl-pentyl-1-oxy)-6-methoxy-phthalazine.8. A compound by the name of6-methoxy-1-phenyl-5-(tetrahydro-furan-2-yloxy)-phthalazine.